CN1879619A - Cancer treatment - Google Patents

Cancer treatment Download PDF

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Publication number
CN1879619A
CN1879619A CNA2006100819920A CN200610081992A CN1879619A CN 1879619 A CN1879619 A CN 1879619A CN A2006100819920 A CNA2006100819920 A CN A2006100819920A CN 200610081992 A CN200610081992 A CN 200610081992A CN 1879619 A CN1879619 A CN 1879619A
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Prior art keywords
carcinoma
cancer
independently
phenyl
furyl
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Inventor
邓哲明
郭盛助
李芳裕
潘秀玲
顾记华
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YONGXIN MEDICINES AND CHEMICAL REAGENTS CO Ltd
Carlsbad Technology Inc
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YONGXIN MEDICINES AND CHEMICAL REAGENTS CO Ltd
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract

This invention relates to a method for treating cancer including administrating to a subject in need thereof an effective amount of a compound of the formula: wherein, A is H or each of Ar 1 , Ar 2 , and Ar 3 , independently, is phenyl, thienyl, furyl, pyrrolyl, pyridinyl, or pyrimidinyl; each of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 , independently, is R, nitro, halogen, C(O)OR, C(O)SR, C(O)NRR', (CH2)mOR, (CH2)mSR, (CH2)mNRR' , (CH2)mCN, (CH2)mC(O)OR, (CH2)mCHO, (CH2)mCH=NOR, (CH2)mC(O)N(OR)R', N(OR)R', or R 1 and R 2 together, R 3 and R 4 together, or R 5 and R 6 together are O(CH 2 ) m O, in which each of R and R', independently, is H or C 1 ~C 6 alkyl; and m is 0, 1, 2, 3, 4, 5, or 6, and n is 0, 1, 2, or 3.

Description

Treatment of cancer
Related application
The application submits in the part continuation application of the U. S. application serial number 10/147,445 on May 16th, 2002 and requires its priority.Its requires to submit in both priority of the U. S. application serial number 10/147,445 on March 29th, 2002 and U.S. Provisional Application number 60/368,892.
Background
Blood vessel takes place, and the formation of neovascularity takes place in healthy body with at the healing following injury wound and recover blood flow in tissue.The blood vessel generating process is closely controlled by various positive regulating factors and negative growth factor.In the numerous disease state, health has been lost the control that blood vessel is taken place.
Too much angiogenic growth can be caused by some pathological condition such as cancer, degeneration of macula, rheumatoid arthritis and the psoriasis relevant with the age.As the result that too much blood vessel takes place, neovascularity supplies nutrients to diseased tissue and destroys normal structure.In cancer, neovascularity permission tumor cell is escaped in the blood circulation and is positioned in other organ.
Blood vessel takes place to take place by a series of consecutive steps, comprises the division and the migration of the endotheliocyte that forms blood vessel wall.Known about 15 kinds of protein activate endothelial cell growth and move.Therefore, blood vessel takes place can be by these activator proteins, for example, and angiogenin, epidermal growth factor, estrogen, fibroblast growth factor, interleukin 8, PGE1 and E2, tumor necrosis factor, VEGF, or the inhibitor of granulocyte colony-stimulating factor suppresses.
With too much blood vessel relevant disease taking place comprises cancer (solid tumor and hematology's tumor), cardiovascular disease (for example, atherosclerosis), chronic inflammatory disease (for example, rheumatoid arthritis or segmental enteritis), diabetes (for example, diabetic retinopathy), psoriasis, endometriosis and obesity.See, for example, Pharmacological Reviews 52:237-268,2001.The chemical compound that effectively suppresses the blood vessel generation is treatment or prevents the drug candidate of these diseases.
General introduction
The present invention is based on wonderful discovery, and promptly many fused pyrazolyl compounds have the effect of angiogenesis inhibitor and suppress the growth of some cancerous cell line.
Thereby feature of the present invention is a kind of treatment method for cancer, and this method comprises chemical compound from the following formula of effective dose to its experimenter of needs that use:
Figure A20061008199200061
Wherein A be H or
Ar 1, Ar 2And Ar 3In each be phenyl independently, thienyl, furyl, pyrrole radicals, pyridine radicals, or pyrimidine radicals; R 1, R 2, R 3, R 4, R 5, and R 6In each be R independently, nitro, halogen, C (O) OR, C (O) SR, C (O) NRR ', (CH 2) mOR, (CH 2) mSR, (CH 2) mNRR ', (CH 2) mCN, (CH 2) mC (O) OR, (CH 2) mCHO, (CH 2) mCH=NOR, (CH 2) mC (O) N (OR) R ', N (OR) R ', or R 1And R 2Together, R 3And R 4Together, or R 5And R 6Be O (CH together 2) mO, wherein each among R and the R ' is H or C independently 1～C 6Alkyl, m are 0,1,2,3,4,5, or 6; And n is 0,1,2, or 3.(CH 2) mCan be side chain or straight chain.Notice at the atom and the fused pyrazole ring on the left side shown in the group of any above-mentioned replacement the most approaching.Be also noted that when one or more R or (CH are arranged in fused pyrazolyl compounds 2) mDuring part, described R or (CH 2) mPart can be identical or different.
A subclass of above-claimed cpd be those wherein A be
Chemical compound; R 1, R 2, R 3, R 4, R 5, and R 6In each be R independently, nitro, halogen, C (O) OR, C (O) SR, C (O) NRR ', (CH 2) mOR, (CH 2) mSR, (CH 2) mNRR ', (CH 2) mCN, (CH 2) mC (O) OR, (CH 2) mCHO, (CH 2) mCH=NOR, or R 1And R 2Together, R 3And R 4Together, or R 5And R 6Be O (CH together 2) mO.In some embodiments, Ar 1, Ar 2And Ar 3In each be phenyl or furyl, and R 1, R 2, R 5, and R 6In each be H, halogen (halo), or C 1～C 6Alkyl, n are 1.
Another subclass of above-claimed cpd be those wherein A be
Chemical compound; R 1, R 2, R 3, R 5, and R 6In each be R independently, nitro, halogen, C (O) OR, C (O) SR, C (O) NRR ', (CH 2) mOR, (CH 2) mSR, (CH 2) mNRR ', (CH 2) mCN, (O) OR, (CH 2) mCHO, (CH 2) mCH=NOR, or R 1And R 2Together, or R 5And R 6Be O (CH together 2) mO; R 4Be (CH 2) mC (O) N (OR) R ' or N (OR) R '.In some embodiments, Ar 1, Ar 2And Ar 3In each be phenyl or furyl; And R 1, R 2, R 5, and R 6In each be H, halogen, or C 1～C 6Alkyl; N is 1.
Above-claimed cpd also have another subclass be those wherein A be the chemical compound of H.In some embodiments, Ar 1And Ar 2In each be phenyl or furyl; And R 1, R 2, and R 3In each be H, and R 4Be CH 2(OH) or CO 2CH 3
The example of cancer that can be by said method treatment comprises leukemia, colorectal carcinoma, carcinoma of prostate, pulmonary carcinoma, breast carcinoma and renal carcinoma.
What show below is exemplary compounds used in this invention:
Figure A20061008199200072
Chemical compound 1 chemical compound 2 chemical compounds 3
Chemical compound 4 chemical compounds 5 chemical compounds 6
Figure A20061008199200081
Chemical compound 7 chemical compounds 8 chemical compounds 9
Figure A20061008199200082
Chemical compound 10 chemical compounds 11 chemical compounds 12
Figure A20061008199200083
Chemical compound 13 chemical compounds 14 chemical compounds 15
Chemical compound 16
Term used herein " Ar " refers to aryl and heteroaryl groups.Aryl, for example, phenyl is the hydrocarbon loop systems with at least one aromatic ring.Heteroaryl is the hydrocarbon loop systems with at least one aromatic ring, and described aromatic ring comprises at least one hetero atom such as O, N, or S.The example of heteroaryl includes, but not limited to thienyl, furyl, pyrrole radicals, pyridine radicals and pyrimidine radicals." Ar " can comprise one on its ring, and two, three, or multi-substituent more.Except being assigned to R 1, R 2, R 3, R 4, R 5, and R 6Those (see above) beyond, described substituent group can also be a nitro, C 2～C 6Alkenyl, C 2～C 6Alkynyl, aryl, heteroaryl, cyclic group (cyclyl), or heterocyclic radical.Randomly use C 1～C 6Alkyl, halogen, amino, hydroxyl, sulfydryl, cyano group, or nitro replaces alkyl used herein, alkenyl, alkynyl, alkoxyl, aryl, heteroaryl, cyclic group, and heterocyclic radical.Notice that term " alkyl " had both referred to straight chained alkyl, referred to branched alkyl again.
Above-mentioned fused pyrazolyl compounds comprise chemical compound himself, and if the prodrug of their salt and they is suitably.These salt for example, can form by the interaction between electronegative substituent group on the fused pyrazolyl compounds (for example, carboxylate) and the cation.The cation that is fit to includes, but not limited to sodium ion, potassium ion, and magnesium ion, calcium ion and ammonium cation are such as tetramethyl ammonium.Similarly, the substituent group of positively charged (for example, amino) can form salt with electronegative counter ion.The counter ion that is fit to includes, but not limited to chloride, bromide, iodide, sulfate, nitrate, phosphate, or acetate.The example of prodrug comprises esters and other medicinal derivative, and it can provide above-mentioned fused pyrazolyl compounds after experimenter's administration.
Also belonging in the scope of the invention is a kind of cancer compositions that is used for the treatment of, and it comprises one or more above-mentioned fused pyrazolyl compounds, and this compositions is used for the application of the medicine of cancer in production.
By description and claim, other features, objects and advantages of the present invention will be conspicuous.
Describe in detail
The fused pyrazolyl compounds that is used for implementing the inventive method can be prepared (see, for example, U.S. Patent number 5,574,168) by well known to a person skilled in the art method.They comprise following route of synthesis: at first by arylcarboxylic acid chlorides and another kind of aryl compound coupling are prepared the aryl aryl ketones.Arbitrary aryl compound randomly is mono-substituted or polysubstituted.Described ketone subsequently with the aryl alkyl hydrazine reaction, the aryl of described aryl alkyl hydrazine also randomly is mono-substituted or polysubstituted, contains the hydrazone of three aromatic yl groups with formation.Described hydrazone groups is changed into fused pyrazole base core by the alkylidene joint, and another aromatic yl group condenses on the 4-C and 5-C of pyrazolyl core, and the 3rd aromatic yl group is directly connected on the 3-C of pyrazolyl core.By the substituent group on the known modification aromatic yl group that is converted, can obtain the derivant of fused pyrazolyl compounds.For example, by the Reducing agent that is fit to methoxycarbonyl group group (CO 2Me) change into methylol groups (CH 2OH).As another example, the methoxycarbonyl group group is hydrolyzed into carboxylic acid, and (COOH), it is converted into subsequently and has more reactive group, acyl chlorides (C (O) X).Described acyl chlorides can with ammonium or azanol reaction to form amide group (C (O) NH 2) or hydroxamic acid group (C (O) NHOH).
The chemicals that is used for above-mentioned route of synthesis can comprise, for example, and solvent, reagent, catalyst, protecting group and remove protecting group reagent.Said method can also comprise step in addition before or after the specifically described step of this paper, to add or to remove the protecting group that is fit to so that finally allow synthetic fused pyrazolyl compounds.In addition, various synthesis steps can be implemented to provide required chemical compound with alternative order or order.The synthetic chemistry conversion and the protecting group methodology (protect and go and protect) that are used for synthetic applicable fused pyrazolyl compounds are well known in the art and comprise, for example, at R.Larock, Comprehensive Organic Transformations, VCH publisher (1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, second edition, JohnWiley ﹠amp; Sons (1991); L.Fieser and M.Fieser, Fieser and Fieser ' s Reagentsfor Organic Synthesis, John Wiley ﹠amp; Sons (1994); And L.Paquette, editor, Encyclopedia of Reagents for Organic Synthesis, John Wiley ﹠amp; Described in Sons (1995) and the subsequent editions thereof those.
Synthetic fused pyrazolyl compounds like this can be passed through such as column chromatography, high pressure lipuid chromatography (HPLC), or recrystallization is further purified.
Feature of the present invention is a kind of treatment method for cancer, comprises one or more fused pyrazolyl compounds from effective dose to its experimenter of needs and the pharmaceutical carrier of using.Term " treatment " refers to use or use the compositions that comprises one or more fused pyrazolyl compounds and gives the experimenter, described experimenter has cancer, cancer symptoms, or cancer tendency, the purpose of using or using is to treat, cure, relax, alleviate, change, remedy, improve, improve or influence described cancer, cancer symptoms, or the cancer tendency." effective dose " refers to fused pyrazolyl compounds after being applied to the experimenter who needs it, gives experimenter's therapeutic effect necessary amount.Be familiar with as those skilled in the art, effective dose can change according to route of administration, excipient usage with the common probability of using of other reagent.
As used herein, " cancer " phalangeal cell tumor.Cancerous cell has the ability of autonomous growth, that is, a kind of abnormality or situation is characterized in that the growth of fast breeding sexual cell.This term is intended to comprise the cancerous growths or the oncogenic process of all types, the tissue of transfer or the cell of vicious transformation, tissue or organ, and irrelevant with the stage of histopathology type or intrusion.The example of cancer comprises, but be not limited to, cancer and sarcoma such as leukemia, sarcoma, osteosarcoma, lymphoma, melanoma, ovarian cancer, skin carcinoma, carcinoma of testis, gastric cancer, cancer of pancreas, renal carcinoma, breast carcinoma, carcinoma of prostate, colorectal carcinoma, head and neck cancer, the brain cancer, esophageal carcinoma, bladder cancer, adrenocortical carcinoma, pulmonary carcinoma, bronchogenic carcinoma, carcinoma of endometrium, nasopharyngeal carcinoma, cervical cancer or hepatocarcinoma, or the cancer in unknown former site.
In order to implement method of the present invention, can be by oral, parenteral is by sucking spray or using fused pyrazolyl compounds by the storage of implanting.When being used for this paper, term " parenteral " comprises subcutaneous, Intradermal, and intravenous, intramuscular, intraarticular, intra-arterial is in the synovial membrane, in the breastbone, in the sheath, in the infringement and intracranial injection or infusion techniques.
Liquid preparations for oral administration can be any oral acceptable forms, includes, but not limited to tablet, capsule, Emulsion and aqueous suspension, dispersion and solution.The common carrier of tablet comprises lactose and corn starch.Also, add tablet such as magnesium stearate typically with lubricant.For the oral administration of capsule form, useful diluent comprises lactose and exsiccant corn starch.When aqueous suspension or Emulsion when Orally administered, can or be dissolved in the oil phase active component and emulsifying agent or suspending agent combined suspension.If desired, can add some sweeting agent, fumet or coloring agent.
Can use suitable dispersant or wetting agent (such as, Tween 80 for example) and suspending agent, according to the compositions (for example, aqueous or oil-based suspension) of technology preparation sterile injectable known in the art.The preparation of sterile injectable can also be the solution or the suspension of the sterile injectable in atoxic parenteral acceptable diluent or solvent, for example, and as the solution of 1,3 butylene glycol.In operable acceptable excipient and solvent, mannitol is arranged, water, Ringer's mixture and isotonic sodium chlorrde solution.In addition, can be with aseptic fixedly oil easily as solvent or suspension media (for example, synthetic monoglyceride or diglyceride).Fatty acid effectively is used in the preparation of injection such as oleic acid and glyceride ester derivatives thereof, and natural medicinal oil such as olive oil or Oleum Ricini, especially with their polyoxyethylene form, also can effectively be used in the preparation of injection.These oil solutions or suspension can also comprise long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersant.
Can prepare composition for inhalation and can be prepared as solution in the saline according to well-known technology in the pharmaceutical formulations field, use benzyl alcohol or other antiseptic that is fit to, increase the absorption enhancer of bioavailability, fluorocarbon, and/or other solubilizing agent known in the art or dispersant.
Carrier in the pharmaceutical composition must in compatible with the active component of described preparation (and preferably, can make its stable) and can not to be harmful on the experimenter's to be treated meaning be " acceptable ".For example, solubilizing agent can be used as drug excipient to be used to send fused pyrazolyl compounds such as cyclodextrin (itself and fused pyrazolyl compounds form special, more soluble complex).The example of other carrier comprises colloidal silica, magnesium stearate, cellulose, sodium lauryl sulphate, and D﹠amp; CYellow#10.
The external test that is fit to can be used for the effect of preliminary assessment fused pyrazolyl compounds in the activity that is suppressed to fibroblast growth factor (FGF) or VEGF (VEGF).Can also carry out measuring to screen effective fused pyrazolyl compounds in the body according to method well-known in the art.See, below specific embodiment.
Similarly, the external test that is fit to can be used for the effect of entry evaluation fused pyrazolyl compounds in the anticancer growth.Can also be by measuring the effect of the described fused pyrazolyl compounds treatment of further research cancer in the body.For example, the animal (for example, mouse model) that chemical compound can be applied to suffer from cancer is also then estimated its therapeutic effect.Based on described result, can also determine the dosage range and the route of administration that are fit to of pyrazolyl compounds.
Do not need other detailed description, think that foregoing description has been enough to make the present invention to implement.Therefore, specific embodiments subsequently should be regarded as only illustrating, and limits the remainder of present disclosure absolutely not by any way.With all publications, comprise that the patent that this paper quotes all incorporates this paper into as a reference.
Synthesizing of 1-benzyl-3-(5 '-methylol-2 '-furyl) indazole (chemical compound 1)
At first by among anhydrous THF (20mL) the stirring anhydrous calcium chloride (88.8mg, 0.8mmol) and sodium borohydride (60mg 1.6mmol) prepared hydroboration calcium in 4 hours.The 30mL THF solution that then will comprise 88.0mg 1-benzyl-3-(5 '-methoxycarbonyl group-2 '-furyl) indazole (0.27mmol) dropwise adds the hydroboration calcium solution in 30 ± 2 ℃.Under refluxing,,, be quenched in the trash ice, remove THF thereby under reduced pressure place, and its filtration is obtained solid product its cooling with described mixture heated 6 hours.With the described solid of dichloromethane extraction.Extract is concentrated to 50mL and solid precipitation after adding petroleum ether.Collect described precipitate and carry out purification to obtain 1-benzyl-3-(5 '-methylol-2 '-furyl) indazole of 70.0mg by column chromatography (silica gel-benzene), productive rate is 87%.
mp：108-109℃.
MS(％)，m/z：304(M +)
IR(KBr)v max：3350cm -1(-OH).
1H-NMR (DMSO-d 6, 200MHz) δ: 4.51 (2H, d, J=5.5Hz ,-CH 2O-), 5.31 (1H, t, J=5.5Hz ,-OH), 5.70 (2H, s ,=NCH 2-), 6.48 (1H, d, J=3.4Hz, H-4 '), 6.97 (1H, d, J=3.4Hz, H-3 '), (7.21-7.31 6H, m, H-5, phenyl), 7.45 (1H, t, J=8.2Hz, H-6), 7.75 (1H, dd, J=8.2,1.8Hz, H-7), 8.12 (1H.dd, J=8.2,1.0Hz, C4-H).
The synthetic inhibition of DNA
Lack chemical compound 1 (substrate (basal) and contrast) or having incubation Human umbilical vein endothelial cells (HUVECs) under chemical compound 1 (concentration is 0.1 μ M, 0.03 μ M, 0.1 μ M, 0.3 μ M, or the 1 μ M) situation.It is synthetic with inducing DNA to add VEGF (VEGF) or basic fibroblast growth factor (bFGF) (except substrate), its based on [ 3H] mixing of thymidine detect.Described result shows that chemical compound 1 suppresses the cell proliferation of VEGF-and the inductive HUVECs of bFGF-in concentration dependent form mode.Unexpectedly, chemical compound 1 has 9.0 * 10 respectively for VEGF and bFGF -8M and 1.4 * 10 -7The IC of M 50Value.
23 kinds of other fused pyrazolyl compounds have also been tested.They all suppress the cell proliferation of the inductive HUVECs of VEGF, and some are identical with the effectiveness of chemical compound 1.
The inhibition that pipe forms
HUVECs is cultivated on the cavate microscope slide, and (Matrigel) (10mg/mL) carries out pre-coating with the cavate microscope slide with matrigel.Handle cell without chemical compound 1 (contrast) or with chemical compound 1 (10 μ M).Adding VEGF (10ng/mL) or bFGF (10ng/mL) induces pipe to form.All photos are taken with 100 x magnifications.Described result shows that the network that chemical compound 1 suppresses the inductive elongated endotheliocyte of VEGF-and bFGF-forms.
The inhibition of angiogenic effect
Come the subcutaneous injection nude mice with the matrigel thromboembolism (plug) that comprises 150ng/mL VEGF or bFGF.With excipient or chemical compound 1 by oral administration to mice 7 days (1mg/kg/ days, 3mg/kg/ days, 10mg/kg/ days, 30mg/kg/ days, or 100mg/kg/ days).Monitor the angiogenic reaction by transparent skin vision.Matrigel itself does not excite the angiogenic reaction.After 7 days, the matrigel thromboembolism is put to death and observed in position to mice to quantize the inside growth of blood vessel.Thromboembolism is removed, be fixed in 4% the formaldehyde, be embedded in the paraffin and be cut into 5-μ m slab and carry out histologic analysis, and quantize vessel growth by hematoxylin-eosin staining.All photos are taken with 40 x magnifications.Described result shows that chemical compound 1 oral administration 7 days has effectively suppressed VEGF or the inductive angiogenic effect of bFGF in the dose dependent mode.
In the quantitative analysis of angiogenic effect, as above handle nude mice, and described thromboembolism is taken out and dissolving.Use hemoglobin detection kit (Sigma Chem.Co.) to measure the index of hemoglobin concentration as angiogenesis.Described result illustrates chemical compound 1 and effectively suppresses VEGF or the inductive angiogenic effect of bFGF.
Inhibitory action to growth of cancers
With A549 lung tumor cell (10 7Individual cell/mice) subcutaneous injection BALB/c-nu mice.After inoculation 29 days, each tumor growth is to 30-50mm 3Size.Mice is divided into 2 groups.Thereby multiple pyrazolyl compounds all is dissolved in sampling solution (1mg/ml) in 0.5% carboxymethyl cellulose separately.From the 29th day, every kind of solution is Orally administered to mice (for pyrazolyl compounds, 10mg/kg/ days) every day, and the size of every 3-4 days measurement tumors.At the 53rd day, come mice is carried out euthanasia with the administration of pentobarbital intraperitoneal.With described ablation of tumors and weigh.
The result shows, unexpectedly, compares with the mice of handling with excipient, has littler tumor with chemical compound 1,12 and 14 mices of handling.
Also detected the inhibitory action of multiple pyrazolyl compounds to the growth of other cancerous cell according to method similar to the above, described cancerous cell, i.e. NCI-H226 (lung carcinoma cell), A 498 (kidney cancer cell), ACHN (kidney cancer cell), UO-31 (kidney cancer cell), HA22T (hepatoma cells), HT-29 (colorectal cancer cell), HCT-116 (colorectal cancer cell), PC-3 (prostate gland cancer cell), MDA-MB-468 (breast cancer cell), and CCRF-CEM (leukaemia).
Described result shows chemical compound 1,10,11,15 and 16 effectively suppress the growth of NCI-H226 cell, chemical compound 1,3,5-7,11, effectively suppress the growth of A 498 cells with 13-16, chemical compound 2 effectively suppresses the growths of ACHN cells, chemical compound 1,2,4 and 6 effectively suppress the growth of UO-31 cell, chemical compound 7 effectively suppresses the growth of HT-29 cell, chemical compound 1,2, with the 5 effectively growths of inhibition HCT-116 cell, and chemical compound 1,4, effectively suppress the growth of PC-3 cell with 6-8, chemical compound 1 effectively suppresses the growth of MDA-MB-468 cell, and chemical compound 1,3,4,6,8 and 9 effectively suppress the growth of CCRF-CEM cell.Be unexpectedly, 1 pair of A498 cell of chemical compound, the rejection ratio of NCI-H226 cell and the growth of MCF-7 cell is more effective to the inhibitory action of HA22T cell growth.
Other embodiment
Disclosed in this manual all features can make up with any combination.Disclosed in this manual each feature can alternative features that is identical by being used for, of equal value or similar purpose be replaced.Therefore, unless clearly point out in addition, disclosed each feature only is the example of the general series of equivalence or similar features.
From foregoing description, those skilled in the art can easily determine essential feature of the present invention, and under the prerequisite that does not deviate from the spirit and scope of the invention, make it be adapted to all usages and situation thereby can make various changes and improvements to the present invention.For example, the chemical compound that structurally is similar to fused pyrazolyl compounds can also be used to implement the present invention.Therefore, other embodiment also belongs in the scope of claim.

Claims (33)

1. treatment method for cancer, this method comprise the compound administration of the following formula of effective dose in its experimenter of needs:
Figure A2006100819920002C1
Wherein
Ar 1, Ar 2And Ar 3In each be phenyl independently, thienyl, furyl, pyrrole radicals, pyridine radicals, or pyrimidine radicals;
R 1, R 2, R 3, R 4, R 5, and R 6In each be R independently, nitro, halogen, C (O) OR, C (O) SR, C (O) NRR ', (CH 2) mOR, (CH 2) mSR, (CH 2) mNRR ', (CH 2) mCN, (CH 2) mC (O) OR, (CH 2) mCHO, (CH 2) mCH=NOR, or R 1And R 2Together, R 3And R 4Together, or R 5And R 6Be O (CH together 2) mO, wherein each among R and the R ' is H or C independently 1～C 6Alkyl, m are 0,1,2,3,4,5, or 6; And n is 0,1,2, or 3;
Described cancer is a leukemia, colorectal carcinoma, carcinoma of prostate, pulmonary carcinoma, breast carcinoma, or renal carcinoma.
2. the process of claim 1 wherein Ar 1It is phenyl.
3. the method for claim 2, wherein Ar 2It is 5 '-furyl.
4. the method for claim 3, wherein Ar 3It is phenyl.
5. the method for claim 4, wherein R 1, R 2, R 5, and R 6In each be H.
6. the method for claim 5, wherein n is 1.
7. the method for claim 6, wherein R 3And R 4One of them is substituted on 2 of furyl.
8. the method for claim 7, wherein R 3And R 4One of them is H, and another is CH 2OH.
9. the process of claim 1 wherein Ar 2It is 5 '-furyl.
10. the method for claim 9, wherein R 3And R 4One of them is substituted on 2 of furyl.
11. the method for claim 10, wherein Ar 3It is phenyl.
12. the process of claim 1 wherein that described cancer is a leukemia.
13. the process of claim 1 wherein that described cancer is a colorectal carcinoma.
14. the process of claim 1 wherein that described cancer is a carcinoma of prostate.
15. the process of claim 1 wherein that described cancer is a pulmonary carcinoma.
16. the process of claim 1 wherein that described cancer is a breast carcinoma.
17. the process of claim 1 wherein that described cancer is a renal carcinoma.
18. the method for claim 8, wherein said cancer is a renal carcinoma.
19. the method for claim 8, wherein said cancer is a pulmonary carcinoma.
20. the method for claim 8, wherein said cancer is a pulmonary carcinoma.
21. a treatment method for cancer, this method comprise the compound administration of the following formula of effective dose in its experimenter of needs:
Wherein
Ar 1, Ar 2And Ar 3In each be phenyl independently, thienyl, furyl, pyrrole radicals, pyridine radicals, or pyrimidine radicals;
R 1, R 2, R 3, R 5, and R 6In each be R independently, nitro, halogen, C (O) OR, C (O) SR, C (O) NRR ', (CH 2) mOR, (CH 2) mSR, (CH 2) mNRR ', (CH 2) mCN, (O) OR, (CH 2) mCHO, (CH 2) mCH=NOR, or R 1And R 2Together, or R 5And R 6Be O (CH together 2) mO, and R 4Be (CH 2) mC (O) N (OR) R ' or N (OR) R '; Wherein each among R and the R ' is H or C independently 1～C 6Alkyl, and m is 0,1,2,3,4,5, or 6; And n is 0,1,2, or 3.
22. the method for claim 21, wherein said cancer is a leukemia, colorectal carcinoma, carcinoma of prostate, pulmonary carcinoma, breast carcinoma, or renal carcinoma.
23. the method for claim 22, wherein Ar 1It is phenyl.
24. the method for claim 23, wherein n is 1 and Ar 3It is phenyl.
25. the method for claim 24, wherein Ar 2It is phenyl.
26. the method for claim 25, wherein R 4Be C (O) N (OR) R '.
27. the method for claim 21, wherein said cancer are pulmonary carcinoma or renal carcinoma.
28. a treatment method for cancer, this method comprise the compound administration of the following formula of effective dose in its experimenter of needs:
Figure A2006100819920004C1
Wherein
Ar 1And Ar 2In each be phenyl independently, thienyl, furyl, pyrrole radicals, pyridine radicals, or pyrimidine radicals;
R 1, R 2, R 3, and R 4In each be R independently, nitro, halogen, C (O) OR, C (O) SR, C (O) NRR ', (CH 2) mOR, (CH 2) mSR, (CH 2) mNRR ', (CH 2) mCN, (CH 2) mC (O) OR, (CH 2) mCHO, (CH 2) mCH=NOR, (CH 2) mC (O) N (OR) R ', or N (OR) R ', or R 1And R 2Together or R 3And R 4Be O (CH together 2) mO, wherein each among R and the R ' is H or C independently 1～C 6Alkyl, and m is 0,1,2,3,4,5, or 6; And n is 0,1,2, or 3.
29. the method for claim 28, wherein said cancer is a leukemia, colorectal carcinoma, carcinoma of prostate, pulmonary carcinoma, breast carcinoma, or renal carcinoma.
30. the method for claim 28, wherein Ar 1It is phenyl.
31. the method for claim 30, wherein Ar 2It is 5 ' furyl.
32. the method for claim 31, wherein R 1, R 2, and R 4In each be H, and R 3Be CH 2(OH) or CO 2CH 3
33. the method for claim 32, wherein said cancer is a leukemia, renal carcinoma, hepatoma, or colorectal carcinoma.
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